Hydroxyurea Facilitates Manifestation of Disease Relevant Phenotypes in Patients-Derived IPSCs-Based Modeling of Late-Onset Parkinson’s Disease

Abstract

Induced pluripotent stem cells (iPSCs)-derived dopaminergic neurons might be reset back to the fetal state due to reprogramming. Thus, it is a compelling challenge to reliably and efficiently induce disease phenotypes of iPSCs-derived dopaminergic neurons to model late-onset Parkinson’s disease (PD). Here, we applied a small molecule, hydroxyurea (HU), to promote the manifestation of disease relevant phenotypes in iPSCs-based modeling of PD. We established two iPS cell lines derived from two sporadic PD patients. Both patients-iPSCs-derived dopaminergic neurons did not display PD relevant phenotypes after 6 weeks culture. HU treatment remarkably induced ER stress on patients-iPSCs-derived dopaminergic neurons. Moreover, HU treatment significantly reduced neurite outgrowth, decreased the expression of p-AKT and its downstream targets (p-4EBP1 and p-ULK1), and increased the expression level of cleaved-Caspase 3 in patients-iPSCs-derived dopaminergic neurons. The findings of the present study suggest that HU administration could be a convenient and reliable approach to induce disease relevant phenotypes in PD-iPSCs-based models, facilitating to study disease mechanisms and test drug effects.

Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

“…Using a well-established midbrain DA neuron differentiation protocol with some minor modifications 19,20 , we successfully generated the floor plate (FP) cells and mature A9 group DA neurons from control and PLA2G6 D331Y/D331Y iPSCs (Fig. 1a).…”

“…1a). Human UC-H1-iPSCs established in our previous study served as the controls 19,20 . Group A9 is the most densely packed group of DA neurons in the ventrolateral midbrain.…”

Comprehensive Perspectives on Experimental Models for Parkinson’s Disease

“…Overexpression of progerin to induce aging in iPSC-derived DA neurons from patients with PD promotes PD disease phenotypes [ 94 ]. Hydroxyurea-treated DA neurons from patients with sporadic PD can rapidly produce PD-related manifestations in early stages [ 95 ]. These strategies facilitate the manifestation of disease-relevant phenotypes in a PD model based on iPSCs derived from patients.…”

Using induced pluripotent stem cells for modeling Parkinson’s disease

“…Previous studies have indicated that chronic treatment with anticancer drug hydroxyurea (HU) could induce cellular senescence in human fibroblasts[106] and mouse neural stem cells[107] via induction of genes related to DNA damage and repair, mitochondrial dysfunction, and ROS increase. In our recent study[108], we found that HU induced disease phenotypes of sporadic PD-patient-specific iPSC-derived DA neurons. HU treatment significantly reduced neurite outgrowth, expression of p-Akt and its downstream targets (p-4EBP1 and p-ULK1), as well as increased the level of cleaved caspase 3 in iPSC-derived DA neurons from sporadic PD patients.…”